PROJECT SUMMARY/ABSTRACT The development of chimeric antigen receptor T cell therapies (CARTx) for B cell malignancies is a major milestone in cancer immunotherapy with high rates of durable complete remissions. Although cytokine release syndrome and neurotoxicity are the earliest and most dramatic immune related adverse events (irAEs) after CARTx, severe manifestations are transient and only affect a minority of patients. In contrast, on-target, off- tumor depletion of non-malignant B lineage cells affects the majority of patients and all long-term responders. CD19 expression declines as B cells differentiate into plasma cells, whereas BCMA is selectively expressed by plasma cells. Since plasma cells are responsible for maintaining long-lived antibodies and nave/memory B cells are important for generating new immunity, CD19 versus BCMA-CARTx may differentially affect preexisting immunity and vaccine responses. Dr. Hill?s goal is to understand the long-term effects of CARTx on humoral immunity. This proposal incorporates the expertise of an outstanding group of researchers in infectious diseases, immuno-oncology, epidemiology, laboratory medicine, and statistics who are dedicated to ensuring the success of this innovative research proposal. They will leverage their expertise and high-volume immunotherapy programs to achieve the following aims. The first Aim involves a prospective observational cohort study of 130 CARTx recipients (50 adult CD19, 50 pediatric CD19, 30 adult BCMA) with relapse-free survival ?6 months. Dr. Hill will use a novel systematic viral epitope scanning method (VirScan) to longitudinally characterize the antivirome to 206 viral pathogens. These results will describe, and identify correlates of, antivirome diversity metrics at 6- and 12-months post-CARTx. VirScan will allow for a nuanced assessment of the differential impacts of CARTx on humoral immune competence. The second Aim will utilize samples from Aim 1 to determine the effect of CARTx on the durability of preexisting humoral immunity to vaccine-preventable infections and the proportion of patients lacking seroprotection after CARTx. These data will expand on Aim 1 to inform vaccination strategies. In the third Aim, Dr. Hill will perform a prospective observational study of 95 CARTx recipients (50 adult CD19, 25 pediatric CD19, and 20 adult BCMA) to define the frequency and correlates of positive vaccine responses ?6 months after CARTx. Patients will be vaccinated for S. pneumoniae, tetanus, diphtheria, pertussis, H. influenza b, and hepatitis A and B according to institutional guidelines. This proposal will address critical knowledge gaps by employing innovative methods to elucidate the scope of pathogen-specific deficits in humoral immunity, and whether vaccination can mitigate these irAEs, after CARTx. The findings will guide evidence-based strategies for infection prevention, such as vaccination or immunoglobulin replacement, to improve outcomes in this rapidly growing population of high-risk individuals.